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Cellular localization of NRF2 determines the self-renewal and osteogenic differentiation potential of human MSCs via the P53-SIRT1 axis

Authors
 DS Yoon  ;  Y Choi  ;  JW Lee 
Citation
 CELL DEATH & DISEASE, Vol.7 : 2093, 2016 
Journal Title
 CELL DEATH & DISEASE 
Issue Date
2016
MeSH
Adult ; Cell Differentiation/physiology ; Cell Proliferation/physiology ; Cells, Cultured ; HEK293 Cells ; Humans ; Mesenchymal Stromal Cells/cytology* ; Mesenchymal Stromal Cells/metabolism* ; NF-E2-Related Factor 2/metabolism* ; Osteogenesis/drug effects ; Osteogenesis/physiology ; Phosphorylation ; Sirtuin 1/metabolism* ; Tumor Suppressor Protein p53/metabolism*
Abstract
NRF2 (nuclear factor erythroid-derived 2-like 2) plays an important role in defense against oxidative stress at the cellular level. Recently, the roles of NRF2 in embryonic and adult stem cells have been reported, but its role in maintaining self-renewal and differentiation potential remains unknown. We studied the mechanisms of NRF2 action in mesenchymal stem cells (MSCs) derived from human bone marrow. We found that the cellular localization of NRF2 changed during prolonged cell passage and osteogenic differentiation. Blocking the nuclear import of NRF2 using ochratoxin A (OTA) induced the loss of the self-renewal and osteogenic potential of early-passage (EP) MSCs. Conversely, reinforcing the nuclear import of NRF2 using tert-butylhydroquinone (t-BHQ) improved the self-renewal capacity and maintained the differentiation potential in the osteogenic lineage of EP MSCs. Real-time quantitative PCR and western blot analysis showed that NRF2 positively regulates sirtuin 1 (SIRT1) at the mRNA and protein levels via the negative regulation of p53. The self-renewal and osteogenic potential suppressed in OTA-treated or NRF2-targeting small hairpin RNA (shRNA)-infected EP MSCs were rescued by introducing small interfering RNA (siRNA) targeting p53. t-BHQ treatment in late-passage (LP) MSCs, which lost their self-renewal and osteogenic potential, reversed these effects. In LP MSCs treated with t-BHQ for ∼7 days, the phosphorylation and nuclear localization of NRF2 improved and SIRT1 protein level increased, whereas p53 protein levels decreased. Therefore, our results suggest that NRF2 plays an important role in regulating p53 and SIRT1 to maintain MSC stemness. This study is the first to establish a functional link between NRF2 and SIRT1 expression in the maintenance of MSC self-renewal and differentiation potential.
Files in This Item:
T201601085.pdf Download
DOI
10.1038/cddis.2016.3
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Orthopedic Surgery (정형외과학교실) > 1. Journal Papers
Yonsei Authors
Lee, Jin Woo(이진우) ORCID logo https://orcid.org/0000-0002-0293-9017
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/146688
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